Peptides as Therapeutic Agents for Dengue Virus

Chew, Miaw-Fang; Poh, Keat-Seong; Poh, Chit-Laa

DENV infection in humans starts with a DENV-infected mosquito bite. DENV can replicate in a wide spectrum of cells, including liver, spleen, lymph node, kidney and other organs [31, 32] , but monocytes, macrophages and dendritic cells (DC) have been shown to be the major targets for DENV [33, 34] . The life cycle of dengue virus is initiated by the virus attachment through the interaction between viral surface proteins and attachment/receptor molecules on the surface of the target cell ( Figure 2 ). Receptor recognition is believed to be mediated by the domain III of E protein to enable the virus to enter into host cells by receptor-mediated, clathrin-dependent endocytosis (primary method) [35, 36] . However, studies have also shown that viral entry could occur by the direct fusion of the virus and host cells [37] [38] [39] . After internalization, dissociation of the E homodimers takes place as a result of the acidic environment in the endosome. Subsequently, domain II of the E protein will project outwardly and the hydrophobic fusion loop in domain II will insert itself into the endosomal membrane [40, 41] . This will then trigger domain III to fold back and force the virus particle and endosomal membrane to move towards each other and fuse together [42, 43] . The fusion of the virus with vesicular membranes would then release the nucleocapsid into cytoplasm, resulting in genome uncoating [44] . Subsequently, the viral RNA genome is released. The viral RNA is translated into a single polyprotein and processed co-and post-translationally by cellular and virus-derived proteases into three structural proteins and seven NS proteins ( Figure 1 ). Upon protein translation, the NS proteins initiate viral genome replication at the intracellular membranes, resulting in the production of more viral RNA strands [45] . Then, the newly synthesized RNA is packed by C proteins to form the nucleocapsid [46] . The prM and E proteins, on the other hand, form heterodimers that oriented into the lumen of ER and are believed to induce a curved surface lattice which guides virion budding [47] . Hence, the virus assembles and buds from the ER before migrating to the trans-Golgi for maturation process. The slightly acidic pH of the trans-Golgi network prompts the dissociation of prM/E heterodimers to form 90 dimers with prM capping the fusion peptide located at the domain II of the E protein [48] . This is followed by the cleavage of the prM at Arg-X-(Lys/Arg)-Arg by cellular endoprotease (furin), (where X is any amino acid) to produce membrane-associated M and "pr" peptide [49, 50] . Both prM and the "pr" will act as chaperones to stabilize the E protein during the secretory pathway by preventing premature membrane fusion. At the end, the "pr" peptide will dissociate upon the release of the progeny by exocytosis [45] .